Back to Search
Start Over
Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2020 Jul 03; Vol. 295 (27), pp. 9033-9051. Date of Electronic Publication: 2020 May 14. - Publication Year :
- 2020
-
Abstract
- Cytochrome P450 1A1 (CYP1A1) catalyzes the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) and is transcriptionally regulated by the aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) complex upon exposure to PAHs. Accordingly, inhibition of CYP1A1 expression reduces production of carcinogens from PAHs. Although transcription of the CYP1A1 gene is known to be repressed by transforming growth factor-β (TGF-β), how TGF-β signaling is involved in the suppression of CYP1A1 gene expression has yet to be clarified. In this study, using mammalian cell lines, along with shRNA-mediated gene silencing, CRISPR/Cas9-based genome editing, and reporter gene and quantitative RT-PCR assays, we found that TGF-β signaling dissociates the B[a]P-mediated AhR/ARNT heteromeric complex. Among the examined Smads, Smad family member 3 (Smad3) strongly interacted with both AhR and ARNT via its MH2 domain. Moreover, hypoxia-inducible factor 1α (HIF-1α), which is stabilized upon TGF-β stimulation, also inhibited AhR/ARNT complex formation in the presence of B[a]P. Thus, TGF-β signaling negatively regulated the transcription of the CYP1A1 gene in at least two different ways. Of note, TGF-β abrogated DNA damage in B[a]P-exposed cells. We therefore conclude that TGF-β may protect cells against carcinogenesis because it inhibits CYP1A1-mediated metabolic activation of PAHs as part of its anti-tumorigenic activities.<br />Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.<br /> (© 2020 Nakano et al.)
- Subjects :
- A549 Cells
Animals
Aryl Hydrocarbon Receptor Nuclear Translocator genetics
Aryl Hydrocarbon Receptor Nuclear Translocator metabolism
Benzo(a)pyrene toxicity
COS Cells
Chlorocebus aethiops
Cytochrome P-450 CYP1A1 metabolism
Gene Expression genetics
Gene Expression Regulation genetics
HEK293 Cells
Humans
Hypoxia-Inducible Factor 1 metabolism
Polycyclic Aromatic Hydrocarbons metabolism
Pyrenes
Signal Transduction
Smad3 Protein metabolism
Transforming Growth Factor beta physiology
Cytochrome P-450 CYP1A1 genetics
Receptors, Aryl Hydrocarbon metabolism
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 295
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32409577
- Full Text :
- https://doi.org/10.1074/jbc.RA120.013596